Atopic dermatitis (AD) is a genetically determined, reaginically (IgE) associated, chronic disease of the skin in which the skin is dry, easily irritated, allergen predisposed, typically scaly, often thickened, commonly red, sometimes exudative, frequently infected and above all itchy. In the United States prevalence rates in childhood range from 8.7 to 18.1% with higher rates in metropolitan areas and among the more affluent. (J Invest Dermatol 131:67-73, 2011). AD may persist into or reappear in adulthood, but may also arise in adult life. (J Am Acad Dermatol 52:579-82, 2005). In industrialized countries, the prevalence rates in childhood range from 15 to 30% and in adults from 2 to 10% of the general population. (NEJM 358:1483-94, 2008). AD adversely affects the quality of life of the patients and their families and imposes a significant financial burden measured in billions of dollars (J Manag Care Pharm 13:349-59, 2007).
Atopic dermatitis is characterized both by a defective skin barrier, the stratum corneum, and by a defective immune response, characterized by Th2 dominance. In the former case, disease pathogenesis follows an outside-to-inside pathway and in the latter case, disease pathogenesis follows an inside-to-outside pathway. (J Invest Dermatol 128:1067-1070, 2008).
Pursuant to outside-to-inside pathogenesis, there are 2 main attributes of the defective skin barrier. One of these attributes results from a deficiency in ceramides, the main lipid in the stratum corneum. Ceramide deficiency characterizes patients with AD, noting that ceramides consist of a union between long chain fatty acids (FA) and sphingosine (S) bases. There is a significant reduction in esterified omega-OH-FA and sphingosine base (EOS), in esterified omega-OH-FA and 6-OH-sphingosine base (EOH), in esterified omega-OH-FA and phytosphingosine base (EOP), in non-OH-FA and 6-OH-sphingosine base (NH), and in non-OH-FA and phytosphingosine base (NP). (J Invest Dermatol 130:2511-14, 2010). The esterified omega-OH-ceramides exist in free and in bound forms—the latter being bound to proteins of the keratinocytic cornified envelope, mostly involucrin. In non-lesional and yet more in lesional skin of patients with AD, there is a marked reduction of these esterified ceramides bound to the cornified envelope. Similarly there is a marked reduction of free extractable very long chain FA, i.e. >24 carbon atoms, both in non-lesional and more severely in lesional skin of patients with AD. These defects contribute to the barrier impairment seen in AD. (J Invest Dermatol 119:166-73, 2002). These changes in ceramide composition are associated with a change in the lamellar lipid organization in AD patients. (J Invest Dermatol 131:2136-38, 2011).
The other main attribute results from genetically induced deficiency in filaggrin, a histadine rich protein whose diminution is found in about ⅓ of patients with AD and in whom clinical severity correlates with transepidermal water loss (TEWL) and poor stratum corneum hydration, whereas similar correlation does not pertain in patients lacking filaggrin deficiency. (J Invest Dermatol 129:682-89, 2008). Yet barrier abnormalities remain in patients with AD lacking filaggrin deficiency, further noting that filaggrin deficiency alone is not sufficient to generate AD as in patients with ichthyosis vulgaris. Nonetheless AD patients with filaggrin mutations have reduced hydroscopic amino acids as well as reduced tight junctions and reduced corneodesmosin, yielding defective intercorneocyte adhesion. These patients manifest persistent disease, a higher incidence of eczema herpeticum, irritant contact dermatitis, allergic contact dermatitis, peanut allergy and asthma. (NEJM 365:1315-27, 2011). Further, filaggrin breakdown products include polycarboxylic acids—the lack of which increases stratum corneum pH, which in turn activates serine proteases. These proteases appear to induce corneocytes to release IL-1α and IL-1β from their pro-forms, initiating inflammatory pathways. These proteases may also mediate Th2 inflammation, even in the absence of allergen priming. (J Exp Med 206:1135-47, 2009).
Pursuant to inside-to-outside pathogenesis, Th2 cytokines may impair the skin barrier. Th2 cytokines include IL-4, IL-5, IL-6, IL-10 and IL-13 (J Invest Dermatol Symp Proc 9:23-8, 2004). Among these cytokines, it has been shown that IL-4 not only inhibits ceramide synthesis in cultured keratinocytes (J Invest Dermatol 124:786-92, 2005) but also inhibits epidermal differentiation complex genes, resulting in significantly lower levels of filaggrin, loricrin and involucrin (J Invest Dermatol 130:S116, 2010). Indeed both Th2 cytokines IL-4 and IL-13 inhibit both filaggrin and human β-defensin 3 expression. (J Invest Dermatol 128: 2248-58, 2008). IL-22 is found in AD skin. It, too, down regulates filaggrin expression in keratinocytes. IL-10 down regulates anti-microbial peptide expression in AD (J Invest Dermato 125:738-45, 2005). IL-31, highly expressed in skin samples of AD patients and associated with the itching of AD, inhibits the expression of terminal differentiation markers including filaggrin (J All Clin Immunol 129:426-33, 2012). Further IL-31 treated skin models resulted in increased uptake of allergens of timothy grass and cat dander, demonstrating increased transepidermal penetration of environmental allergens (J Invest Dermatol 132: S78, 2012).
Dendrocytes are increased in number in AD skin and produce IL-25 (IL-17E). IL-25 levels are elevated in the skin of AD patients and it induces and prolongs Th2 immune responses. Specifically, IL-25 induces production of IL-4, IL-5, IL-13, IgE and eosinophilia in a murine model of asthma. In addition to this, IL-25 decreases synthesis of filaggrin in cultured keratinocytes (J Invest Dermatol 131:150-7, 2011). Kallikrein, including kallikrein 7, are serine proteases, elevated in the epidermis of AD patients. Overexpression of human kallikrein 7 in murine epidermis results in a chronic itchy dermatitis. Cultured normal human epidermal keratinocytes treated with IL-4 or IL-13 increased kallikrein levels. Kallikreins 1, 8, 11, 12 and 13 were similarly induced (J Invest Dermatol 130:S47, 2010). Kallikreins elevate tissue pH which impairs glucocerebrosidase and sphingomyelinase—both of which require acidic pH, resulting in impaired ceramide production and impairment of the skin barrier.
It has been shown that Th2 cytokines and Th22 cytokines remain dominant in acute and chronic phases of AD. A claim that acute AD is followed by chronic AD is somewhat of a mischaracterization because AD is almost always a chronic dermatitis in which the patient clinically experiences (acute) flares of AD. Irrespective of such characterization, Th2 cytokines, including IL-4 and IL-10, as well as Th22 cytokines, IL-22 and IL-31, are up regulated in “acute” AD and are increased even more in “chronic” AD such that Th2 and Th22 cytokines are dominant throughout the disease course (J Invest Dermatol 132:S13, 2012).
The frequent chronic infections that occur on and in the skin of AD patients appear to result both from the defective skin barrier of AD and from an impaired immune response, e.g. upon testing with trichophyton antigen, patients with AD show immediate rather than the normal delayed immune response. The most common of the microbes infecting AD skin is Staphylococcus aureus (Staph). In AD skin, Staph induces and exacerbates itching, increases inflammation and provokes oozing and eczematization. Of patients whose skin oozes, 100% will culture out Staph. Of those who do not ooze, the majority will still culture out Staph, although less massively. Staph binds readily to Th2 inflamed skin as compared with Th1 inflamed skin, perhaps accounting for the high colonization rate of AD skin (J Invest Dermatol 116:658-63, 2001).
Staph contributes to AD disease expression. Lipoteichoic acid is a constituent of the cell wall of Staph. It is a potent agonist of platelet-activating factor receptor (PAF-R). Lipoteichoic acid and PAF-R suppress Th1 type reactions but up-regulate production of IL-10, a Th2 cytokine (J Am Acad Dermatol AB12, March 2005), contributing to the Th2 dominant inflammation of AD. Further IL-10 is elevated in both extrinsic and intrinsic forms of AD. IL-10 inhibits the expression of antimicrobial peptides, enabling Staph colonization (J Invest Dermatol 125:738-745, 2005). Staph derived ceramidase may aggravate the skin barrier defect of AD. Staph enterotoxins inhibit the suppressive activity of regulatory T cells and correlate with AD severity. Staph exotoxins up-regulate Th22 cell production of the highly pruritogenic IL-31. About 50% of patients with AD produce IgE directed against Staph toxins and IgE is a chief mediator of Th2 inflammation.
Viruses, too, more readily grow in AD skin than in normal skin. Viruses commonly colonizing AD skin include herpes simplex, verruca vulgaris and molluscum contagiosum.
There is no known cure for AD. The many treatment approaches attest the inadequacy and limitations of each. In briefest outline, these treatments include avoidance of soap, irritants and allergens, hydration of the skin, dietary restrictions, tars, antihistamines, hyposensitization, corticosteroids, antibacterials, antifungals, antivirals, ultraviolet light, leukotriene blockers, inhibitors of mast cell content release, evening primrose oil, Chinese herbal teas, pentoxifylline, pimecrolimus, tacrolimus, azathioprine, cyclosporin A, cyclophosphamide, interferon γ, thymopentin and phosphodiesterase inhibitors. The corticosteroids are most commonly used in clinical practice, but suffer from incomplete responses, tachyphylaxis, induction of atrophy and the potential of suppression of the pituitary-adrenal axis if used widely enough, long enough and potently enough.